Tissue ischemia is a consequence of vaso-occlusive sickle cell disease (SCO). In the current funding cycle, we identified an adverse, long-range consequence of localized ischemia in the sickle milieu:. SCO transforms and disseminates a localized, regional, and otherwise self-remitting ischemic insult into a systemic, nflammatory process attended by vaso-occlusion in distant and vital organs, and ultimately, increased mortality. Tissue ischemia is thus not only a consequence of vaso-occlusive disease but is also a contributor to vaso-occlusion, inflammation, and other pathogenetic pathways in SCO. As in any diseased tissue, adaptive and maladaptive processes are entrained, and in this regard, we hypothesize that in SCO in the unstressed state and in the stressed, postischemic state, a triad of linked responses occurs, and consists of induction of heme oxygenase-1 (HO-1) and p21 as adaptive, protective responses, and induction of monocyte chemoattractant protein-1 (MCP-1) as a maladaptive, injurious process. This theme will be pursued in 4 specific aims: Aim I: Hypothesis: The sickle milieu transforms and disseminates a transient episode of localized ischemia into a systemic, long-range, inflammatory process with widespread vaso- occlusion and dysfunction of distant vital organs. Examination: Alterations in vital organs and tissues, and relevant systemic indices will be analyzed in sickle mice in the unstressed state and following regional ischemia. Aim II: Hypothesis: Induction of HO-1 is an adaptive, protective response in SCO in the unstressed state and following regional ischemia. Examination: Deficiency of HO-1. in the endothelium and kidney using a Cre/lox approach will exacerbate injury in these sites in sickle mice in the unstressed state and following regional ischemia. Aim III: Hypothesis: Induction of MCP-1 (a HO-suppressible gene) is a maladaptive, injurious response in SCO in the unstressed state and following regional ischemia. Examination: Approaches that interrupt either the expression of MCP-1 gene or the efficacy of the MCP-1 protein will decrease tissue injury in sickle mice in the unstressed state and following regional ischemia. Aim IV: Hypothesis: Induction of p21 (an HO-inducible protein) is an adaptive, protective response in SCO in the unstressed state and following regional ischemia. Examination: Deficiency of p21, as modeled by p21 -/- mutant mice, will exacerbate tissue injury in sickle mice in the unstressed state and following regional ischemia. LAY SUMMARY: Decreased blood supply to tissues contributes to organ and tissue damage in sickle cell disease. This application proposes to study how this occurs, and the genes that are induced, specifically, those such as MCP-1 that contribute to injury, and those such as HO-1 and p21 that protect against such injury. Such information may assist in devising new treatments for sickle cell disease.